This invention relates to the use of (synthetic and modified) laminin receptor-targetted ligands for the treatment of angiogenic diseases such as proliferative retinopathies and metastatic cancer as well as for the treatment of Candida spp. infections, or parastic infestations such as leishmania and trichomonas vaginalis. 
Laminin antagonists (which are anti-angiogenic) can be used to inhibit secondary tumour spread (by inhibiting tumour cell attachment) and to prevent growth of metastatic secondaries (by inhibiting neovascularisation). These antagonists could also be used to treat other angiogenic disorders (such as diabetic retinopathy).
Laminin agonists (which promote angiogenesis) could be used to treat retinopathy of prematurity, and could also be used to promote wound healing (for example in corneal epithelium).
Both the antagonists and the agonists would be expected to inhibit parasite binding to tissue surfaces and would thus prevent infection or infestation.
Angiogenic diseases are those disorders which are directly caused by, or complicated by the inappropriate growth of new blood vessels. The major angiogenic diseases include the common metastatic solid tissue cancers (breast, gastrointestinal, lung, prostatic, etc), diabetic retinopathy, neovascular glaucoma, rheumatoid arthritis and psoriasis. Angiogenesis is the rate-limiting step in the growth of secondary tumours; inhibition of their neovascularisation is known to stop their growth.
In this field it is already known that the native ligand of the 67 kDa laminin receptor (67LR) is encompassed by the linear sequence of amino acids 925–933 of the laminin β-1 (previously known as laminin B1 or b1) chain (numbering refers to the mature murine laminin β-1). Synthetic laminin β-1925-933 (single letter amino acid code: CDPGYIGSR-NH2) (SEQ ID NO: 1) has been shown to inhibit tumour establishment in mice, by inhibiting attachment of tumour cells to basement membranes. It has also been demonstrated that laminin β-1925-933 inhibits angiogenesis in the chick.
However, synthetic laminin-derived peptide (laminin β-1925-933) stimulates angiogenic events in mammalian cells (in which it acts as a pure 67LR agonist), making it useless as the basis of a human therapy.
It is one object of the present invention to provide a medicament to treat angiogenic diseases.
The present invention provides a peptide factor derived from murine epidermal growth factor (EGF) peptide for use in the preparation of a medicament for the treatment of angiogenic diseases.
The mechanism by which EGF derived peptides inhibit new blood vessel formation is through their antagonism of the high affinity 67 kDa laminin receptor (67LR) found on endothelial cells.
The peptides have the additional effect of inhibiting tumour cell attachment to basement membranes, and may be used to prevent solid cancer spread in cases where cancer cells have been identified circulating in the blood.
Modified peptides may be protected from proteolytic degradation by substitution of key residues with unnatural amino acid analogues at susceptible bonds, such as tyrosine analogues (at position 5) and arginine analogues (at position 9). The peptides may be capped at N- and C-termini (with acetyl and amide groups respectively) and at the thiol groups of the cysteines (with acetamido methyl groups).
Typically the peptide is an antagonist of the 67 kDa Laminin Receptor (67LR).
The peptide factor is based on amino acid residues 33 to 42 of murine epidermal growth factor (mEGF).
The amino acid sequence of mEGF-(33–42) is CVIGYSGDRC (SEQ ID NO: 2).
Preferably the sequence of peptide factor is modified from the natural sequence to protect the peptides from protease attack.
Preferred substitutions include the use of tyrosine analogues at position 5 (SEQ ID NO: 3) and arginine analogues at position 9 (SEQ ID NO: 4).
Preferably the peptide factor is capped at the N terminal with an acetyl group (SEQ ID NO: 5).
Preferably the peptide factor is capped at the C terminal with an amide group (SEQ ID NO: 6).
Preferably the thiol groups of cysteines are capped with acetamido methyl groups.
In one embodiment the synthetic peptide has the sequence                Acetyl-C-[S-Acm]-VIGYSGDR-C-[S-Acm]NH2 (SEQ ID NO: 7)        
A preferred tyrosine analogue is Tic-OH (SEQ ID NO: 8).
A preferred arginine analogue is Citrulline (SEQ ID NO 9).
The structure of Citrulline and other potential arginine analogues are shown below.